Patients with life-threatening hematologic disorders can be cured by blood, marrow and cord blood transplantation, but face major impediments. Life-threatening post-transplant complications can still occur despite HLA matching; when matched stem cell sources are not available, the criteria for selecting the least risky mismatched allograft are not known. Patients who tolerate the transplant procedure remain at risk for disease recurrence. As the global transplant experience matures, patient/donor ethnicity has been recognized as an important determinant of post-transplant outcomes. We hypothesized that the MHC and KIR genetic regions harbor functional variants that are not currently tested in routine clinical practice. We have identified SNP variants within the MHC that influence the success of HLA matched and mismatched transplantation, and have elucidated the importance of KIR diversity and KIR-HLA interactions on outcomes. We now propose to examine the underlying mechanisms of these genotype associations with transplant outcomes. We will leverage large, ethnically diverse transplant populations to 1) validate SNPs and determine the mechanisms for SNP-associated mortality; 2) determine the role of expression in defining permissible HLA-A mismatches; 3) determine how expression and specificity of KIR3DL1/HLA-Bw4 interactions influence NK function and outcomes; 4) determine how allotype interactions between HLA-C specific KIR and HLA-C ligands impact outcomes, and 5) determine the rank order of immunogenetic factors that most strongly predict survival. These research questions will address the current roadblocks in alternative donor transplantation and provide novel information that can be translated to clinical practice for patients of diverse racial background.